PROJECT ABSTRACT The overall goal of this K99/R00 Application is to improve our understanding of the genetic and molecular control of bone remodeling by identifying a novel regulator, elucidating its modes of action and documenting its therapeutic importance. This application will examine (1) the role of brain-derived serotonin in the regulation of bone formation and its mechanisms of action;(2) the functional hierarchy between brain-derived and gut-derived serotonin;(3) the therapeutic potential of inhibiting the synthesis of gut-derived serotonin;(4/5) the implications of alterations in the serotonin levels through synthetic serotonin reuptake inhibitors (SSRIs) during pre- and postnatal period in skeletogenesis and acquisition of bone mass accrual, and (6) and the role of melatonin in the regulation of bone remodeling. The first three aims of this project will be done under the mentorship of Dr. Gerard Karsenty while the last three aims will be done in the independent phase of this application. The coordination of these projects and a smooth transition from K99 to R00 phase of this application will be performed by the program director in consultation with Dr. Gerard Karsenty. This will be facilitated, due to the synergy and at the same time diversity between the K99 and R00 parts of this application, by continuous interactions. Together, these studies should provide important and novel insights into the genetic and molecular control of bone remodeling as well as in the pathogenesis and treatment of osteoporosis, a major disease of aging. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Serotonin is a hormone/ neurotransmitter that has attracted a tremendous amount of attention because of its ability to regulate several neuroendocrine/ endocrine functions. In the context of the recent demonstration of an endocrine pathway regulating bone remodeling through gut-derived serotonin, it is important to understand the effect of brain-derived serotonin in the regulation of bone mass. This is a critically important question if one wants to use this pathway to design novel anabolic drugs for treatment of osteoporosis. This project will explore genetically and in vivo, the therapeutic implications of gut-derived serotonin and whether brain-derived serotonin and its metabolite melatonin regulate bone mass.